Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH:6]=1)=[O:4].CO.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[O:17])[CH:19]=1
Reactant: COC(=O)c1ccc(=O)n(CCCNC(=O)c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(=O)n(CCCNC(=O)c2cccnc2)c1

Procedure:
1,6-dihydro-1-[3-(3-pyridinylcarbonylamino)propyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.18 g, 0.57 mmol) was hydrolysed in a mixture consisting of methanol (0.7 ml), water (0.7 ml), and 15% aqueous sodium carbonate (0.7 ml) at 60° C. for 1.3 hours. The solution was acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: 218°-220° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH2:13][C:14](=O)[CH2:15][CH3:16].N1CCCC1>CO>[CH2:13]([C:14]1([CH2:15][CH3:16])[CH2:9][C:8](=[O:10])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[O:11]1)[CH3:12]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCC(=O)CC
Solvent: CO
Solvent: C1CCNC1
Product: CCC1(CC)CC(=O)c2cc(F)ccc2O1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
1-(5-Fluoro-2-hydroxyphenyl)ethanone (30.2 g, 196 mmol) and MeOH (300 mL) were stirred at ambient temperature and 3-pentanone (41.6 mL, 392 mmol) and pyrrolidine (17.8 mL, 216 mmol) were added. The mixture was heated to 60° C. for 62 h at which point LCMS analysis showed clean conversion to product. The reaction was cooled, concentrated to a minimal volume of MeOH, and MTBE (300 mL) was added. The organics were washed with 2N HCl (150 mL), brine (60 mL), 2N NaOH (150 mL), and brine (60 mL). The solution was passed through a plug of silica gel (30 g), washing with MTBE (150 mL). The filtrate was concentrated, giving the title compound (38.8 g, 175 mmol, 89%) as a light brown oil. MS (DCI/NH3) m/z 240 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[CH:36]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc5cc[nH]c45)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 7-formylindole to the procedure of step 1, Example 66. MS (ES) m/z 506.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=C([CH:18]=[C:19]([F:21])[CH:20]=1)C#N)=[N:9][NH:8][C:7]2=[O:22].[OH-:23].[K+].[CH2:25]([OH:27])[CH3:26]>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:26]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:25]([OH:23])=[O:27])=[N:9][NH:8][C:7]2=[O:22]
Reactant: [OH-]
Reactant: N#Cc1cc(F)cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Reactant: CCO
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(F)cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Temperature: 100 °C
Yield: 96 %

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-fluorobenzonitrile (127) (1.26 g, 4.02 mmol) and potassium hydroxide (2.253 g, 40.16 mmol) were added to ethanol (30 mL) and water (70 mL) and heated at 100° C. for 5 hours. The ethanol was evaporated off and the aqueous was extracted with ethyl acetate (1×75 mL). The aqueous was then acidified to pH1 with conc HCl to afford a solid, this was filtered, washed with water and dried to afford the desired compound as a beige solid (1.280 g, 96% yield); 1H NMR (400.132 MHz, DMSO) δ 4.69 (2H, s), 7.35 (1H, d), 7.50 (1H, d), 7.58 (1H, s), 7.82 (1H, t), 7.99 (1H, d), 8.34 (1H, d), 12.87 (1H, s); m/z (LC-MS, ESI+), RT=0.99 (M+H 333).
Reaction SMILES: [N:1]([C@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:23][CH2:22][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[N+]=[N-].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:1][C@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CC1=C(N2CCC3(CCN(C[C@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(N2CCC3(CCN(C[C@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-8-(2-azido-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (250 mg, 0.54 mmol) in a mixed solvent of tetrahydrofuran and water (v:v, 12:1, 20 mL) was added triphenylphosphine (283 mg, 1.08 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation and the residue was purified by preparative TLC (dichloromethane: methanol=10:1) to afford the title compound. 1H NMR (400 MHz, Methanol-d4): δ 7.80 (d, J=8.0 Hz, 1H), δ 7.66 (d, J=8.0 Hz, 1H), 5.40 (s, 2H), 5.24 (s, 2H), 4.73 (dd, J=4.0 Hz, 8.8 Hz, 1H), 4.09 (t, J=6.8 Hz, 2H), 3.30-3.21 (m, 1H), 2.98-2.91 (m, 1H), 2.87-2.81 (m, 1H), 2.70-2.66 (m, 1H), 2.55-2.47 (m, 2H), 2.40 (s, 3H), 2.18-2.07 (m, 4H), 2.00 (s, 3H), 1.74-1.68 (m, 2H). MS-ESI (m/z): 440 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][NH2:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([NH:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:23]=[C:17]12
Reactant: NCc1cc(F)c(F)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(NCc1cc(F)c(F)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (3,4,5-trifluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[N+](C1C=C(Cl)C(Cl)=CC=1C[C:28]([N:30](C)[C@@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)CC[C@H:32]1[N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O)([O-])=O.[C:50]([NH:57][C:58]1[CH:63]=[CH:62][C:61]([CH2:64][C:65]([OH:67])=O)=[CH:60][CH:59]=1)([O:52][C:53]([CH3:56])(C)C)=[O:51].N1C=CC=CC=1.Cl>O>[CH2:53]([O:52][C:50]([NH:57][C:58]1[CH:59]=[CH:60][C:61]([CH2:64][C:65]([N:30]([CH3:28])[C@@H:31]([C:40]2[CH:35]=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)[CH2:32][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:67])=[CH:62][CH:63]=1)=[O:51])[CH2:56][CH2:1][CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1N1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCOC(=O)Nc1ccc(CC(=O)N(C)[C@H](CN2CCCC2)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
This compound was prepared via the general DCC/pyr coupling method from 8 (1.9948 g, 8.001 mmol), N-Boc-4-aminophenylacetic acid (3.0589 g, 12.173 mmol), DCC(2.6602 g, 12.89 mmol), and pyridine (1.04 mL, 12.9 mmol). The crude product was gravity column chromatographed eluting with CH2Cl2:2% NH3:1% MeOH before it was converted to the HCl salt with 1.0 M HCl in Et2O and crystallized from MeOH to yield 18HCl.(0.4891 g, 12%, first crop): m.p. (HCl salt) 170° C. (dec); 1H NMR (HCl salt, DMSO-d6) δ1.49 (s, 9H, t-butyl), 2.01 (br s, 4H, —CH2CH2—), 2.83 (s, 3H, —NCH3), 3.1-4.15 (complex, 8H, 4 —CH2—), 6.27 (m, 1H, —CH—), 7.17 (d, J=8 Hz, 2H, aromatic), 7.39 (d, J=8 Hz, 2H, aromatic), 7.7 (m, 2H, aromatic), 8.09 (s, 1H, aromatic), 8.23 (d, J=6 Hz, 1H, aromatic), 9.3 (s, 1H, —NHBoc). MS(FAB) 483. Anal. (C, H, N) C26H34N4O5HCl.0.25 H2O.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][C:12]1[N:13]=[C:9]([N:8]2[C:3](=[O:22])[CH:4]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:5][C:6]2=[S:7])[S:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc(C)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(N2C(=O)C(Cc3ccccc3)NC2=S)n1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
A solution of N-[[(4-methyl-2-thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (0.94 g, 2.80 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 216.1 mg (25%) of the titled product:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:28])=O.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:28])[C:11]2[C:16]([C:17]=1[OH:18])=[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2cccc(-c3ccccc3)c2c1O
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2cccc(-c3ccccc3)c2c1O
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
411 mg of 1,4-Dihydroxy-5-phenyl-isoquinoline-3-carboxylic acid butyl ester, from Example D-39c isomer B, was suspended in 15 ml of anhydrous acetonitrile. 2.0 g of phosphorous oxybromide was added and the reaction mixture was heated to reflux for 3.5 h. The reaction mixture was cooled and poured into 75 ml of 0° C. saturated aqueous sodium bicarbonate solution. The mixture was stirred for 5 min and then extracted with 75 ml portions of ethyl acetate three times. The combined organic fractions were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue (434 mg) was purified by chromatography on silica gel using a gradient of 0 to 25% ethyl acetate in hexanes to elute the product as one major fraction. 480 mg of the desired product was obtained; MS (+): m/z 422.02 (M+23)
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:30]([NH:32][CH:33](OC)[C:34]([OH:36])=[O:35])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CO>O1CCOCC1>[NH:1]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C

Procedure:
Mix Boc-Ser(OBn)-Phe-Val-Gly(OMe), SEQ ID NO:23, (3.95 g, 6.45 mmol), 1 N sodium hydroxide (39 mL, 39 mmol), methanol (100 mL) and dioxane (60 mL). Stir at room temperature under a nitrogen atmosphere until hydrolysis is complete. Evaporate the solvent in vacuo and purify by silica gel chromatography (chloroform) to give Boc-Ser(OBn)-Phe-Val-Gly, SEQ ID NO:25, (3.32 g, 85.4%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([Cl:19])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O
Product: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To 5.00 g (22.7 mmol) of 4,4'-difluorobenzhydrol was added 16.5 ml (227 mmol) of thionyl chloride in the atmosphere of argon, and the mixture was stirred at room temperature for 30 minutes. To the resulting mixture was added water followed by extraction with benzene. The organic layer was successively washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to column chromatography on silica gel. There was yielded 4.90 g (20.5 mmol) of 4,4'-difluorobenzhydryl chloride from the fraction eluted with benzene.
Reaction SMILES: C1([P+](Cl)(Cl)[Cl:8])C=CC=CC=1.[N+]([C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:17]([O:19][C:20](=[O:21])[C:15]=12)=[O:18])([O-])=O.[OH-].[Na+]>C1(P(Cl)(Cl)=O)C=CC=CC=1>[Cl:8][C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:17]([O:19][C:20](=[O:21])[C:15]=12)=[O:18]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Cl[P+](Cl)(Cl)c1ccccc1
Agent: O=P(Cl)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OC(=O)c2c(Cl)cccc21
Temperature: 170 °C

Procedure:
Phenyltrichlorophosphonium hexachlorophosphide (4 g, 8.8 mM) was added to phenylphosphonic dichloride (10 ml). To this solutoin, 3 nitrophthalic anhydride (1.7 g, 8.8 mM) was added. The reaction mixture was heated to 170° C. for 12 hours, then cooled to room temperature and poured onto ice. After neutralizing with 50% aqueous sodium hydroxide, the reaction was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 3-chlorophthalic anhydride (1.3 g, 81 wt. % yield) as a tan solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[F:17])[CH2:29][CH2:28]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(C(C)(C)C)n1

Procedure:
171 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(2-fluorophenyl)piperazine (81 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[O:33]1[CH2:38][CH:37]=[C:36](B(O)O)[CH2:35][CH2:34]1>>[F:22][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]=2[CH:13]=[C:12]([CH:36]2[CH2:37][CH2:38][O:33][CH2:34][CH2:35]2)[N:11]=1)=[CH:3][C:2]([C:29]1[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)C1=CCOCC1
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2CCOCC2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA11 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and 3,6-dihydro-2H-pyran-4-ylboronic acid MS m/z=467.0 [M+H]+. Calculated for C24H20F2N4O2S: 466.50.
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[C:18]([O-:21])(=[S:20])[CH3:19].[K+].CCOC(C)=O.O>CN(C=O)C>[C:18](=[O:21])([S:20][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])[CH3:19]
Reactant: CC([O-])=S
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)SC(C)C(=O)c1c(C(C)C)nn2ccccc12
Yield: 55.6 %

Procedure:
A solution of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.9 g, 1 equivalent) and potassium thioacetate (0.61 g, 1.5 equivalents) in 4 mL of DMF was stirred at room temperature for 1 hour. The resulting solution was worked up with EtOAc and water. The crude product was purified by silica gel flash column chromatography to give S-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl ethanethioate (0.58 g, 55% yield) as a yellow solid. Compound 1081.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CC(C)(C)C(OI(OC(=O)C(C)(C)C)C1C=CC=CC=1)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:43]=[CH:44][C:45]=1[Cl:46])[CH2:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[C:35]([O:41][CH3:42])[CH:34]=1.ClCCCl>C(OC(C)C)(=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([CH:43]=[CH:44][C:45]=1[Cl:46])[CH2:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:38])=[C:35]([O:41][CH3:42])[CH:34]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C=O
Agent: CC(C)(C)C(=O)OI(OC(=O)C(C)(C)C)c1ccccc1
Solvent: ClCCCl
Solvent: CC(=O)OC(C)C
Product: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C(=O)NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a solution of methanesulphonamide (79.6 mg, 0.837 mmol) and bis[(2,2-dimethylpropanoyl)oxy](phenyl)-lambda-3-iodane (630.0 mg, 1.553 mmol) in isopropyl acetate (6.0 mL) was added 4-[(3,4-dichlorobenzyl)oxy]-2-methoxybenzaldehyde (Preparation 25, 300.0 mg, 0.963 mmol) and 4 Å molecular sieves (500.0 mg). The reaction mixture was stirred for 5 minutes producing a thick suspension. 3,3′-(1,3-Phenylene)bis(2,2-dimethylpropanoic acid)-dirhodium(Rh—Rh) (2:1) (13 mg, 0.017 mmol) was added in one portion and the resulting mixture stirred at room temperature for 10 minutes. 1,2-dichloroethane (5 mL) was then added producing a green solution, which was stirred for further 18 hours under a nitrogen atmosphere at room temperature. The reaction mixture was then concentrated in vacuo and partitioned between DCM and aqueous solution of hydrochloric acid (2 M). The combined organics were dried through a phase separation Cartridge™ and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0 to 60% EtOAc in heptane to yield the title compound as pale yellow gum which solidified upon standing (140 mg, 41% yield):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][OH:22])[O:18][C:17]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[O:18][C:17]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1
Reactant: CN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (900 mg) was dissolved in pyridine (20 ml), and cooled to 0° C. Triethylamine (0.5 ml) and methanesulfonyl chloride (0.24 ml) were added, and stirring continued at 5° C. for 2 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 3% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (990 mg).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH:15]([CH3:20])[CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(Cl)(=O)[C:22](Cl)=[O:23].[I:27][C:28]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[C:29]=1C(O)=O.[K+].[Br-]>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH:15]([CH3:20])[CH2:16][N:17]([CH3:19])[CH3:18])[C:22](=[O:23])[C:36]4[CH:35]=[C:34]([O:37][CH3:38])[C:33]([O:39][CH3:40])=[CH:29][C:28]=4[I:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(CN(C)C)Nc1ccnc2cc3c(cc12)OCO3
Reactant: COc1ccc(I)c(C(=O)O)c1OC
Agent: [Br-]
Agent: [K+]
Product: COc1cc(I)c(C(=O)N(c2ccnc3cc4c(cc23)OCO4)C(C)CN(C)C)cc1OC
Yield: 60.4 %

Procedure:
Prepared from N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane- 1,2-diamine (273 mg, 1.0 mol) in 60.4% yield with a reaction time of 12 h, from the acid chloride prepared using 4.8 mmol of oxalyl chloride and 1.2 mmol of 2-iodo-5,6-dimethoxybenzoic acid. Compound 7b had: mp 82-84° C.; IR (KBr) 1648, 3415; HRMS calcd for C24H26IN3O5H 564.0917; found 564.0997
Reaction SMILES: [Mg].II.Br[CH:5]=[CH:6][CH3:7].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[NH:15][CH:5]=[C:6]2[CH3:7]
Reactant: CC=CBr
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(Br)cccc12
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Magnesium turnings (1.45 g) in dry THF (10 ml) were stirred at room temperature under nitrogen and an iodine crystal added, followed by a few milliliters of a solution of 1-bromo-1-propene (7.25 g, 0.06 mole) in dry THF (50 ml). After warming to initiate the reaction, the remaining bromopropene solution was added dropwise at a rate to maintain reflux. After addition, the reaction was heated at reflux for a further hour, cooled and added rapidly to a stirred solution of 2-bromonitrobenzene (4.04 g, 0.02 mole) in dry THF (70 ml) at -40° C. under nitrogen. The reaction mixture was stirred for a further 30 minutes at -40° C., then was quenched with saturated aqueous ammonium chloride and extracted into diethyl ether. The combined organic extracts were washed with water, dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with 25% diethyl ether in hexane, to yield a yellow-orange oil.